Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies

Abstract

Background and Objectives Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE e4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. Methods We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. Results Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10−8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in e4/e4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10−14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in e3/e4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04–24.64, p ≤ 2.72 × 10−5) than radiographically mild ARIA (OR = 3.19–5.00, p ≤ 1.37 × 10−5) among e4/e4 homozygotes. APOE e4 was also significantly associated with both symptomatic (e4/e4 OR = 3.64–9.52; p < 0.004) and asymptomatic (e4/e4 OR = 4.20–7.94, p < 1.7 × 10−11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. Discussion We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions.